Abstract 411: High Density Lipoprotein (HDL) Loses Endothelial-protective Effects in Patients with Stable Coronary Disease and Acute Coronary Syndrome: Implications for HDL-targeted Therapies
Background: HDL from healthy subjects (HS) exerts direct endothelial-protective effects, such as stimulation of endothelial production of anti-atherogenic nitric oxide (NO). HDL-targeted treatment approaches are currently intensely studied, however, whether HDL from patients with stable coronary disease (sCAD) or an acute coronary syndrome (ACS) exerts endothelial-protective effects remains unknown.
Methods: HDL was isolated by sequential ultracentrifugation from patients with sCAD or ACS (n=26) and HS (n=12). The effects of HDL on endothelial cell NO and TNFα-stimulated superoxide production were determined by ESR spectroscopy analysis. HDL was further injected into nude mice with carotid injury to examine HDL’s in vivo endothelial repair capacity, i.e. re-endothelialized area (REA) after 3 days. HDL’s anti-inflammatory properties were examined by effects on endothelial-monocyte adhesion and endothelial adhesion molecule expression. HDL’s malonylodialdehyde (MDA) levels, a marker of lipid oxidation, and activity of paraoxonase, an HDL-associated antioxidant enzyme, were examined.
Results: HDL from HS increased endothelial cell NO production, in contrast HDL from both, sCAD and ACS patients inhibited endothelial cell NO production (HS: +18±3 vs. CAD −6±4 vs. ACS −11±3%; P<0.05 vs. HS). Endothelial superoxide production was markedly reduced by HDL from HS, but not by HDL from sCAD or ACS patients. Importantly, HDL from HS, but not sCAD or ACS patients accelerated endothelial repair (REA: +14±1%; P<0.05 vs. control). HDL from HS, but not sCAD or ACS patients inhibited endothelial monocyte adhesion. HDL’s MDA levels were markedly increased and HDL’s paraoxonase activity was profoundly reduced in sCAD and ACS patients as compared to HS (60 vs. 20 vs. 370 mU/μg HDL; P<0.01 vs. HS).
Conclusion: These findings suggest for the first time that HDL from patients with stable CAD or ACS loses critical endothelial-protective effects, i.e. the capacity to stimulate endothelial NO production or promote endothelial repair. These observations may have important implications for evaluation of HDL-targeted therapies, since only raising HDL with vasoprotective properties can be expected to exert beneficial cardiovascular protective effects.